Melanotan II and Melanocortin Receptor Signalling in Animal Models: A Research Summary

Melanotan II (MT-II) is a cyclic analogue of α-melanocyte-stimulating hormone that acts as a potent, non-selective agonist at melanocortin receptors, and it has been used extensively as a pharmacological probe of melanocortin signalling in rodents. In a comparative pharmacology study, nine melanocortin ligands were characterised for affinity and potency at cloned rat MC3 and MC4 receptors in vitro and then compared with their ability to induce grooming behaviour in rats; the potency order of MC4 receptor agonists, but not that of MC3 receptor agonists, corresponded to grooming potency after intracerebroventricular administration, and MT-II also induced grooming when given intravenously [1]. A substantial part of the MT-II literature concerns ingestive behaviour and energy balance in rodents. In male rats, chronic central infusion of MT-II produced a severe but transient reduction in feeding, reduced fat pad weight relative to pair-fed animals, and largely cancelled the hyperphagia and adipogenic effects driven by co-infused neuropeptide Y, while leaving NPY-driven suppression of the gonadotropic and somatotropic axes unaffected [2]. In chow-fed and high-fat diet-induced obese rats, six-day central MT-II infusion suppressed caloric intake and reduced body weight and visceral adiposity relative to ad libitum-fed and pair-fed controls, increased oxygen consumption, and was associated with elevated brown adipose tissue UCP1 despite reduced hypothalamic MC3 and MC4 receptor expression in the obese group [3]. In outbred Wistar rats, third-ventricular administration of MT-II at doses matched to leptin for anorexigenic effect produced comparable rises in plasma ACTH and corticosterone and c-Fos labelling in paraventricular CRH neurons; the anorexigenic efficacy of MT-II correlated with paraventricular melanocortin binding and CRH immunoreactivity but not with proneness to diet-induced obesity [4]. In a three-choice feeding model in mice, the non-selective agonist MT-II preferentially decreased fat consumption, and this effect was absent in MC4 receptor-deficient animals [5]. Site-specific work in male C57BL/6J mice showed that bilateral microinjection of MT-II into the nucleus accumbens decreased home-cage and operant consumption and appetitive responding for chow without producing conditioned taste avoidance or altering metabolic rate [6]. Several studies have mapped circuits engaged by melanocortin receptor activation. Whole-cell recordings in mouse brain slices combined with in vivo chemogenetics found that subsets of histidine decarboxylase-expressing tuberomammillary neurons were excited by MT-II through MC4 receptors via a glutamatergic presynaptic mechanism, and that chemogenetic inhibition of these neurons enhanced the anorexigenic effect of intracerebroventricular MT-II [7]. In rats, MT-II delivered into the ventromedial hypothalamus increased oxygen consumption and energy expenditure, lowered the respiratory exchange ratio, raised gastrocnemius heat dissipation, increased skeletal muscle norepinephrine turnover as an index of sympathetic drive, and induced mRNA expression of muscle energetic mediators [8]. In female PACAP-deficient mice undergoing cold acclimation, daily peripheral MT-II partially restored noradrenaline-induced metabolic rate and corrected a deficit in lipid utilisation relative to wild-type controls, which the authors interpreted as PACAP acting upstream of the melanocortin system [9]. A review of brown adipose tissue innervation notes the high colocalisation of MC4 receptor mRNA with central sympathetic outflow neurons identified by transneuronal tracing in rodents, and that fourth-ventricular melanotan II elicited interscapular BAT UCP-1 gene expression in chronically decerebrate animals [10]. MT-II has also been applied in rodent models of ethanol drinking. Using the drinking-in-the-dark procedure, central MT-II blunted binge-like ethanol intake in both wild-type and MC3 receptor knockout mice, with knockout animals showing greater sensitivity, leading the authors to propose that MC3 receptors oppose the effect [11]. In male C57BL/6J mice, MT-II and the opioid antagonist naltrexone each reduced binge-like ethanol drinking and blood ethanol levels, and isobolographic analysis indicated that co-administration increased the effectiveness of naltrexone in a synergistic manner [12]. Other behavioural models have been reported. In male Sprague-Dawley rats exposed to chronic unpredictable stress, daily intraperitoneal MT-II or Semax attenuated stress-induced anhedonia in the sucrose preference test, body weight gain suppression, adrenal hypertrophy and reductions in hippocampal BDNF, with no effect detected on immobility in the forced swim test [13]. In a maternal immune activation mouse model, continuous administration of MT-II over seven days altered social behavioural metrics in adult male offspring, while normal background male mice showed no significant change in social, anxiety-like or repetitive measures, though weight loss was observed after subacute treatment [14]. Studies of sexual behaviour in rodents form a further cluster. In ovariectomised Long-Evans rats primed with estradiol benzoate and progesterone, intravenous MT-II increased hops, darts and ear wiggling in paced mating tests without altering pacing or lordosis, and no effect was seen with estradiol priming alone [15]. In anaesthetised rats, MT-II delivered intravenously or into the paraventricular nucleus elicited erectile events dose-dependently and shortened latency to the first event, facilitated erectile responses to cavernous nerve stimulation after intravenous delivery, showed no facilitator activity after intracavernosal injection, and lost its facilitator effect after removal of the lumbar paravertebral sympathetic chain but not after spinalisation or pelvic and dorsal penile nerve transection [16]. Pharmacological antagonism experiments in rats found that 5-HT2B/2C and selective 5-HT2C receptor antagonists inhibited penile erections elicited by apomorphine, oxytocin or MT-II, which the authors took as evidence that a serotonergic pathway lies downstream of the melanocortin pathway [17]. A review summarising basic and clinical work on melanocortin receptor agonists, including melanotan I, melanotan II and bremelanotide, discusses their investigation in human sexual arousal and erectile disorders and concludes that further investigation is warranted [18]. Outside energy balance and behaviour, MT-II has been examined in a peripheral nerve model: in rats subjected to sciatic nerve crush, subcutaneous MT-II enhanced recovery of sensory function at an intermediate dose but not at lower or higher doses tested, and partially protected the nerve in a cisplatin-induced toxic neuropathy model [19]. Taken together, the cited literature on MT-II is overwhelmingly rodent-based, and the receptor-level findings derive from cloned receptors studied in vitro [1][19].